The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.
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Squaramides represent a class of vinylogous amides that are derived from the squarate oxocarbon dianion. While they have been known since the 1950s, squaramides have only recently emerged (in the last 10–20 years) as particularly useful chemical entities in a variety of applications. They have found particular use as bioisosteric replacements of several heteroatomic functional groups, notably ureas, thioureas, guanidines, and cyanoguanidines, owing in part to their similar capacity toward hydrogen bonding and ability to reliably engender defined conformations in drug ligands. This Review aims to provide a comprehensive overview of the deployment of squaramides as bioisosteres within the drug design landscape. Their utility in this space is further rationalized through an examination of the physicochemical properties of squaramides in contrast to other functional groups. In addition, we consider the deployment of related cyclic oxocarbanion derivatives as potential bioisosteric replacements of ureas and related functional groups.
Acetohydroxyacid synthase (AHAS, EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides, and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Thirteen AHAS inhibiting herbicides have K i values of <2 μM for this enzyme, with the most potent having K i values of <32 nM. Six of these compounds exhibited MIC50 values of <1 μM against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 μM) in defined minimal media. The MIC50 value increases to 0.90 μM in media enriched by the addition of branched-chain amino acids at the expected concentration in the blood serum. The sessile MIC50 for BSM is 0.6 μM. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is nontoxic in HEK-293 cells at concentrations >100 μM and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections.
Dysphania is an abundant genus of plants,m any of which are endemict ot he Australianc ontinent, occurring primarily in arid and temperate zones. Despite their prevalence, very few investigationsi nto the phytochemistry of native Dysphania have been undertaken. Described herein, is the isolation and elucidation of two enantiomeric diastereomers of humulene diepoxide Cf rom D. kalpari and D. rhadinostachya,o fw hich unassigned diastereomerso fh umulene diepoxide Ch ave been previously reported as components in beer brewedf rom aged hops. In addition, two (+)-humu-lene diepoxiols (humulene diepoxiol C-I and C-II) were isolated from D. rhadinostachya. Analysis of Chinook hopso il confirmedt he presence of both humulene diepoxide C-I and C-II as trace components, and in turn enabled GC-MSp eak assignment to the relative stereochemistry.A nticancera ssays did not reveal any significant activityf or the (+)-humulene diepoxides. Antifungal assayss howed good activity against ad rug-resistant strain of C. auris,w ith MIC 50 values of 8.53 and 4.91 mm obtainedf or (+)-humulene diepoxide C-I and C-II, respectively.Scheme1.Biosynthesis of the humulene (1)skeleton starting from farnesyl diphosphate (2), including oxidation of 1 to the diepoxides A-E shown with relative stereochemistry.[a] Y.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.
Dysphania is a genus of plants endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very little in the way of phytochemical and/or bioactivity investigation of native Dysphania has been performed. Herein reported is the isolation and elucidation of (6E,9E)-zerumbone epoxide and a hitherto unreported isomer, (6Z,9E)-zerumbone epoxide, from D. kalpari. In addition, a novel isodaucane sesquiterepene, kalparinol, was isolated from both D. kalpari and D. rhadinostachya. The coisolation of the humulene and isodaucane skeletons, combined with the lack of any cadalane systems, could suggest an alternate novel biogenetic pathway originating from zerumbone, which is unlike any other proposals for the isodaucene system.
Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A ( 6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5−8 are not associated with the reported toxicity of this plant species.Cynanchum is a large genus of plants belonging to the Apocynaceae family (milkweed family, formerly Sarcostemma 1,2 ), consisting of over 200 species distributed worldwide. 3 Cynanchum species have long been used in Asia as traditional medicine for the treatment of common and chronic diseases. 3 Australia is home to around 13 native species of Cynanchum, occurring most commonly in northern Australia, 1,2,4 and certain species, in particular C. viminale subsp. australe (R.Br.) Mere & Liede, are known to have been used by Aboriginal peoples for the treatment of several conditions, including the topical treatment of wounds, cuts, and sores. 5 In addition, crude extracts of C. viminale subsp. australe have been reported to display cancer cell line cytotoxicity activity 6 and are especially active against skin cancer. 7 Interestingly, C. viminale subsp. australe has been reported to display toxicity toward livestock to varying extents all depending on location and/or drought, 8 which is also the case for a closely related Australian species, C. brevipedicellatum. 1 Livestock toxicity has also been observed in South Africa arising from other Cynanchum species and subspecies of C. viminale and was attributed to an abundance of pregnane glycosides 9,10 in the plant latex, such as sarcovimisides A−C (1−3) from C. viminale 11 and cynafoside A (4) from C. af ricanum 12 (Figure 1). Structurally, pregnane glycosides consist of a C 21 pregnane aglycone with a hydroxy group at C-3 and a substituent at C-17 and typically also contain an additional O-linked substituent at C-12. 9,10 The glycoside unit is typically comprised of a linear chain of mixed sugars, commonly glucose, rhamnose, and dideoxy sugars such as oleandrose, cymarose, or digitoxose. 9,10 While the most common aglycone motif within this family is 14β-hydroxypregnane, an increasing number of 14,15-and 8,14-seco-pregnane aglycones have been reported, along with a wider range of pharmacological effects. 13 Considering that very early attempts were unable to fully elucidate saponins from C. viminale subsp. australe, 14 and the Cynanchum genus aligns with our continued effort...
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